The Central Importance of Hub Proteins in a Disease-Gene Network Model: A New Paradigm of Chronic Myeloid Leukemia Disease Study

2021 ◽  
Author(s):  
K M Taufiqur Rahman ◽  
Md. Fahmid Islam ◽  
Sanjib Saha ◽  
Md. Morsaline Billah
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Drug Target ◽  
Disease Gene ◽  
Cellular Communication ◽  
Interaction Pattern ◽  
Node Degree ◽  
Topology Analysis ◽  
Gene Set

Background: The network biology of disease-gene association provides a holistic framework to decipher the intrinsic complexity of disease signaling pathways into cellular communication level. Different types of studies including large-scale genome-wide association, multifactor dimensional reduction analysis, whole genome, or exome-based sequencing strategies of diseases are striving to connect genes to diseases. Indeed, these approaches have had some accomplishments, but the cellular communication level needs a more streamlining outcome to understand the mechanistic impact of context. The higher-order combination of disease-gene interaction has a great potential to decipher the intricateness of diseases. The molecular interaction pattern of diseases at the genomic and proteomic level offers a revolutionized platform not only to understand the complexity of particular disease modules and pathways but also leading towards design novel therapeutics. Results: The enrichment and topology analysis was performed by JEPETTO a plugin of Cytoscape software. We identified the chronic myeloid leukemia (CML) disease signaling pathways that appeared first in the ranking order based on XD-score among the bone, breast, and colon genes set and second at kidney and liver. This result validates the highest proximity between CML and five cancerous tissue gene set clusters. The topology analysis also supports the results while (p<0.0001) is considered to be extremely significant between CML and fives cancerous tissues genes set. Enrichment analysis identified that abl-gene acts as an overlapping node which is the major gene for inducing various mutations in CML. Amazingly, we identified 56 common path expansion/added genes among these five cancerous tissues which can be considered the direct cofactors of CML disease. By relative node degree, resolution, possible ligand, stoichiometry, Q-mean, and Z-score analysis we found 11 hubs proteins like SMAD3, GRB2, TP53, SMAD4, RB1, HDAC1, RAF1, ABL1, SHC1, TGFBR1, RELA which can be regarded for further drug target identification. Conclusions: Our proposed network analysis reflects on the gene set interaction pattern of disease signaling pathways of humans. The integrated multidrug computational and experimental approaches boost up to improve the novel drug target approach. Besides, such a trove can yield unprecedented insights to lead to an enhanced understanding of potential application both in drug target optimization and for drug dislodging.

scholarly journals Characterization of p190-Bcr-Abl chronic myeloid leukemia reveals specific signaling pathways and therapeutic targets

Leukemia ◽  
2020 ◽  
Author(s):  
Shady Adnan-Awad ◽  
Daehong Kim ◽  
Helena Hohtari ◽  
Komal Kumar Javarappa ◽  
Tania Brandstoetter ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Lymphoblastic Leukemia ◽  
High Risk Patient ◽  
Therapeutic Targets ◽  
Hematopoietic Progenitor Cell ◽  
Sensitivity Testing

Abstract The oncogenic protein Bcr-Abl has two major isoforms, p190Bcr-Abl and p210Bcr-Abl. While p210Bcr-Abl is the hallmark of chronic myeloid leukemia (CML), p190Bcr-Abl occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) patients. In CML, p190Bcr-Abl occurs in a minority of patients associating with distinct hematological features and inferior outcomes, yet the pathogenic role of p190Bcr-Abl and potential targeting therapies are largely uncharacterized. We employed next generation sequencing, phospho-proteomic profiling, and drug sensitivity testing to characterize p190Bcr-Abl in CML and hematopoietic progenitor cell line models (Ba/f3 and HPC-LSK). p190Bcr-Abl CML patients demonstrated poor response to imatinib and frequent mutations in epigenetic modifiers genes. In contrast with p210Bcr-Abl, p190Bcr-Abl exhibited specific transcriptional upregulation of interferon, interleukin-1 receptor, and P53 signaling pathways, associated with hyperphosphorylation of relevant signaling molecules including JAK1/STAT1 and PAK1 in addition to Src hyperphosphorylation. Comparable to p190Bcr-Abl CML patients, p190Bcr-Abl cell lines demonstrated similar transcriptional and phospho-signaling signatures. With the drug sensitivity screening we identified targeted drugs with specific activity in p190Bcr-Abl cell lines including IAP-, PAK1-, and Src inhibitors and glucocorticoids. Our results provide novel insights into the mechanisms underlying the distinct features of p190Bcr-Abl CML and promising therapeutic targets for this high-risk patient group.

scholarly journals Effects of Quercetin and Curcumin Combination on Signal Transduction Pathways in Chronic Myeloid Leukemia Cells

Proceedings ◽  
2018 ◽  
Vol 2 (25) ◽  
pp. 1524
Author(s):  
Ergul Mutlu Altundağ ◽  
Ayşe Mine Yılmaz ◽  
Belgin Sert ◽  
Tuğba Erkmen ◽  
Semra Koçtürk ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Chronic Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Synergistic Effects ◽  
K562 Cells ◽  
Leukemia Cells ◽  
Pcr Array ◽  
Normal Peripheral Blood ◽  
Synergistic Combination

Flavonoids have chemo-preventive and chemotherapeutic properties against different human cancers including chronic myeloid leukemia. Quercetin and curcumin are two polyphenols with potential anti-carcinogenic and pro-apoptotic properties. We have previously demonstrated the synergistic protective effect of quercetin and curcumin on chronic myeloid leukemia cells (K562) cells. Anti-proliferative and apoptotic effects of these polyphenols were examined by apoptosis and cell viability assays. Oxidative status of the cells was analyzed by determining the level of reactive oxygen species, mitochondrial permeability and intracellular glutathione. Obtained data showed that quercetin and curcumin had beneficial and synergistic effects on K562 cells. On the basis of the above-mentioned data, herein we aimed to clarify signaling pathways involved in synergistic combination of quercetin and curcumin on K562 cells. Normal peripheral blood mononuclear cell line was used as controls. The mRNA and protein expressions of the signaling pathways were detected by Human Signal Transduction Pathway Finder-RT2 PCR Array system and Western blotting, respectively. The results of PCR array were evaluated by DAVID v6.8 and database for KEGG pathways. Our data revealed that synergistic combination of curcumin quercetin was effective on genes that were particularly related to P53, NF and TGF. We believe that our findings will lead to new research in this area and will contribute to the chronic myeloid leukemia treatment protocols.

A Bio-Integrative Approach Identifies an Inflammatory Signature in Chronic Myeloid Leukemia (CML) Stem Cells That Is Highly Perturbed in CML Blast Crisis and Involves REL transcription Factor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4017-4017
Author(s):  
Christophe Desterke ◽  
Ludovic Marie-Sainte ◽  
Amine Sbitti ◽  
Ali Naama ◽  
Annelise Bennaceur-Griscelli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factor ◽  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Integrative Approach ◽  
Hematopoietic Stem ◽  
Gene Set

Abstract Chronic myeloid leukemia is a clonal myeloproliferative neoplasm defined by the presence of BCR-ABL fusion gene. This oncogenic event occurs in a hematopoietic stem cell (HSC) involved in CML initiation, maintenance, relapse and progression. Several evidences suggest that inflammatory pathways may participate to the pathophysiology of CML as well as disease progression to blast crisis. It has been shown that NFKB/REL pathway is constitutively activated both in BCR-ABL positive leukemic cell lines as well as in primary blast cells from CML-BC patients. More recent works identified IL6 as key cytokine acting on CML multipotent progenitors and their normal bystander counterpart to favor their differentiation toward the myeloid lineage. In addition, high levels of autocrine TNFα secretion by quiescent CML stem/progenitor cells activate NFKB pathway and promote their survival. Although all of these observations are linked to inflammatory processes, a focused analysis of inflammatory pathways in primary CML stem cells has not been performed so far. In the present study we undertook a text-mining strategy using pubmed e-querying to generate an exhaustive set of genes linked to inflammation. Then we integrated transcriptome analysis of highly purified CML stem cells to evaluate the contribution of these genes in CML development and progression. Methods : We queried 6 key words (Inflammation, macrophages, inflammatory response, chemokines, leukocytes and interleukins) that returned a total of 332000 hits in Pubmed. A raw gene set of 918 genes was found significantly associated (p<0.05) with these hits. Using R-package, we applied a false discovery rate correction that decreased the set to 588 relevant genes. The expression level of this gene set was then analyzed in previously reported microarray data (GEO accession: GSE47927) of highly purified normal cord blood CD34+CD38-CD90+ HSCs (CB; n=3), chronic phase (CP; n= 6), accelerated phase (AP; n =4) and Blast crisis (BC; n=2) CML cells. Results: Among the 588 genes related to inflammation we found 70 genes differentially expressed between the four groups (normal, CP, AP and BC, p<0.01; ANOVA test). Enrichment analysis confirmed 29 up regulated genes (NES = 2.12; p<0.0001) among which IL-6, PARP1, IL1R2, IRF5, IRF8, IL20. 39 genes such as STAT3, STAT4, CD47, CXCR4 IL-11, IL15, TLR-1, were down-regulated in CML CD34+CD38-CD90+ (all phases) as compared with normal HSCs (NES = -2,58; p<0.0001). Using principal component analysis on the 70 inflammatory deregulated genes we identified 10 genes such as IRAK1, IL1R2, VEGF and ESAM that discriminate "all phase" CML samples from normal HSCs (Dim 2 = 22.7%). Another inflammatory gene subset (n=26 genes) comprising IL6, REL, CXCR4, CXCL2, IL11, TLR1, IL1R2, PPARA highly separated CML stem cells according to the disease phase. The later gene set highly separates CP and AP-CML stem cells from BC-CML stem cell (Dim 1 = 50.3%). We next performed a random forest analysis with machine learning (1000 trees) and found that the inflammatory transcript level that best predicted CML phase was REL transcription factor. The expression of 413 genes were found positively correlated with REL expression in CP, AP and BC-CML CD34+CD38-CD90+ cells (r>0.75 and p-value <0.001). A search using JASPAR and TRANSFAC database identified a significant enrichment of NFKB1 and RELA binding motif in the promoter regions of these 413 genes (p<0.00001) among which several regulatory factors of hematopoietic stem cell biology. Conclusion : Using a bio-integrative approach we identified a specific inflammatory signature in CD34+CD38-CD90+ CML stem cells. This inflammatory network is highly altered in blast crisis suggesting its contribution to disease evolution. We identified REL overexpression as a good predictor for disease progression to blast crisis and found NFKB1and RELA (p=3.2x10-13) as the best REL target candidates. RELA/NFKB1 was previously shown to be constitutively activated in CML and Ph+ ALL and this analysis suggests that this may also take place in the most primitive subset of CML cells although REL may be the main partner of NFKB in CML stem cells. These results which are currently validated using functional assays, could lead to identification of novel therapeutic strategies. Disclosures Turhan: Bristol Myers Squibb: Consultancy; Novartis: Research Funding.

scholarly journals MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia

Oncotarget ◽  
2016 ◽  
Vol 7 (27) ◽  
pp. 42683-42697 ◽  
Author(s):  
Chiranjib Chakraborty ◽  
Ashish Ranjan Sharma ◽  
Bidhan Chandra Patra ◽  
Manojit Bhattacharya ◽  
Garima Sharma ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Mapk Signaling ◽  
Mapk Signaling Pathways

scholarly journals DIA-based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

2021 ◽  
Author(s):  
wei liu ◽  
Yaoting Sun ◽  
weigang ge ◽  
fangfei zhang ◽  
lin gan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Target ◽  
Acquired Resistance ◽  
Resistance Index ◽  
K562 Cells ◽  
Resistance Mechanisms ◽  
Acquired Drug Resistance ◽  
Proteome Changes

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia (CML). To understand the underlying resistance mechanisms in response to imatinib (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for two months to generate derivative cells with mild, intermediate and severe resistance to the drugs as defined by their increasing resistance index (RI). PulseDIA-based quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7,082 proteotypic proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin Signaling Pathway was found to be significantly enriched in both ADR- and IMA-resistant K562 cells. In particular, IDH2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated IDH2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.

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